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https://www.readbyqxmd.com/read/28209993/suppression-of-tak1-pathway-by-shear-stress-counteracts-the-inflammatory-endothelial-cell-phenotype-induced-by-oxidative-stress-and-tgf-%C3%AE-1
#1
Ee Soo Lee, Llorenç Solé Boldo, Bernadette O Fernandez, Martin Feelisch, Martin C Harmsen
Endothelial dysfunction is characterised by aberrant redox signalling and an inflammatory phenotype. Shear stress antagonises endothelial dysfunction by increasing nitric oxide formation, activating anti-inflammatory pathways and suppressing inflammatory pathways. The TAK1 (MAP3K7) is a key mediator of inflammation and non-canonical TGF-β signalling. While the individual roles of TAK1, ERK5 (MAPK7) and TGF-β pathways in endothelial cell regulation are well characterised, an integrative understanding of the orchestration of these pathways and their crosstalk with the redox system under shear stress is lacking...
February 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28194669/mir-143-targeting-tak1-attenuates-pancreatic-ductal-adenocarcinoma-progression-via-mapk-and-nf-%C3%AE%C2%BAb-pathway-in-vitro
#2
Feng-Ting Huang, Juan-Fei Peng, Wen-Jie Cheng, Yan-Yan Zhuang, Ling-Yun Wang, Chu-Qiang Li, Jian Tang, Wen-Ying Chen, Yuan-Hua Li, Shi-Neng Zhang
BACKGROUND: Transforming growth factor (TGF)-β-activated kinase 1 (TAK1) is one of the major regulators of inflammation-induced cancer cell growth and progression. MiR-143 dysregulation is a common event in a variety of human diseases including pancreatic ductal adenocarcinoma (PDA). AIMS: To identify the interaction between TAK1 and miR-143 in PDA. METHODS: Data mining of TAK1 expression in PDA patient gene profiling was conducted. QRT-PCR and western blot were performed to detect the expression of TAK1 in PDA tissues and cell lines...
February 13, 2017: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/28192731/isotrifoliol-inhibits-pro-inflammatory-mediators-by-suppression-of-tlr-nf-%C3%AE%C2%BAb-and-tlr-mapk-signaling-in-lps-induced-raw264-7-cells
#3
Hua Li, Jeong-Hyun Yoon, Hyo-Jun Won, Hyeon-Seon Ji, Heong Joo Yuk, Ki Hun Park, Ho-Yong Park, Tae-Sook Jeong
Soybeans, produced by Glycine max (L.) Merr., contain high levels of isoflavones, such as genistein and daidzein. However, soy leaves contain more diverse and abundant flavonol glycosides and coumestans, as compared to the soybean. This study investigated the anti-inflammatory effects of the major coumestans present in soy leaf (coumestrol, isotrifoliol, and phaseol) in lipopolysaccharide (LPS)-induced RAW264.7 cells. Coumestans significantly reduced LPS-induced nitric oxide (NO), prostaglandin E2 (PGE2), and reactive oxygen species (ROS) production; isotrifoliol had the most potent anti-inflammatory activity...
February 10, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28182011/tak1-regulates-resident-macrophages-by-protecting-lysosomal-integrity
#4
Yosuke Sakamachi, Sho Morioka, September R Mihaly, Giichi Takaesu, Julie F Foley, Michael B Fessler, Jun Ninomiya-Tsuji
Hematopoietic cell survival and death is critical for development of a functional immune system. Here, we report that a protein kinase, TAK1, is selectively required for resident macrophage integrity during embryogenesis. Hematopoietic lineage-specific deletion of Tak1 gene (Tak1(HKO)) caused accumulation of cellular debris in the thymus in perinatal mice. Although no overt alteration in thymocytes and blood myeloid populations was observed in Tak1(HKO) mice, we found that thymic and lung macrophages were diminished...
February 9, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28111999/enhancement-of-hyperthermia-induced-apoptosis-by-5z-7-oxozeaenol-a-tak1-inhibitor-in-molt-4-cells
#5
Peng Li, Qing-Li Zhao, Paras Jawaid, Mati Ur Rehman, Kanwal Ahmed, Hiroaki Sakurai, Takashi Kondo
PURPOSE: Transforming growth factor-β-activated kinase1 (TAK1) plays an anti-apoptotic role in response to multiple stresses. TAK1 inhibitor, 5Z-7-oxozeaenol (OZ) has been studied for its apoptotic effects. However, the combined effect of OZ with physical stresses remains to be elusive. Therefore, in this study we focussed to determine the combined effects of OZ with hyperthermia (HT) using Molt-4 cell line. MATERIALS AND METHODS: Molt-4 cells were pre-treated with OZ for 1 h followed by heat exposure (44 °C, 10 min) and harvested 24 h after incubation at 37 °C, apoptosis was measured by Annexin V-FITC/PI double staining assay using flow cytometry and cell growth was observed by cell counting assay...
January 22, 2017: International Journal of Hyperthermia
https://www.readbyqxmd.com/read/28109791/identification-of-a-selective-inhibitor-of-transforming-growth-factor-%C3%AE-activated-kinase-1-by-biosensor-based-screening-of-focused-libraries
#6
Takaaki Miura, Atsushi Matsuo, Terushige Muraoka, Mitsuaki Ide, Kenji Morikami, Takayuki Kamikawa, Masamichi Nishihara, Hirotaka Kashiwagi
Transforming growth factor-β activated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase family, plays an essential role in mediating signals from various pro-inflammatory cytokines and therefore may be a good target for developing anti-inflammation agents. Herein, we report our efforts to identify TAK1 inhibitors with a good selectivity profile with which to initiate medicinal chemistry. Instead of resorting to a high-throughput screening campaign, we performed biosensor-based biophysical screening for a limited number of compounds by taking advantage of existing knowledge on kinase inhibitors...
December 29, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28106845/post-translational-modifications-of-the-tak1-tab-complex
#7
REVIEW
Yusuke Hirata, Miki Takahashi, Tohru Morishita, Takuya Noguchi, Atsushi Matsuzawa
Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family that is activated by growth factors and cytokines such as TGF-β, IL-1β, and TNF-α, and mediates a wide range of biological processes through activation of the nuclear factor-κB (NF-κB) and the mitogen-activated protein (MAP) kinase signaling pathways. It is well established that activation status of TAK1 is tightly regulated by forming a complex with its binding partners, TAK1-binding proteins (TAB1, TAB2, and TAB3)...
January 19, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28102840/cancer-associated-fibroblasts-enact-field-cancerization-by-promoting-extratumoral-oxidative-stress
#8
Jeremy Soon Kiat Chan, Ming Jie Tan, Ming Keat Sng, Ziqiang Teo, Terri Phua, Chee Chong Choo, Liang Li, Pengcheng Zhu, Nguan Soon Tan
Histological inspection of visually normal tissue adjacent to neoplastic lesions often reveals multiple foci of cellular abnormalities. This suggests the presence of a regional carcinogenic signal that spreads oncogenic transformation and field cancerization. We observed an abundance of mutagenic reactive oxygen species in the stroma of cryosectioned patient tumor biopsies, indicative of extratumoral oxidative stress. Diffusible hydrogen peroxide (H2O2) was elevated in the conditioned medium of cultured skin epithelia at various stages of oncogenic transformation, and H2O2 production increased with greater tumor-forming and metastatic capacity of the studied cell lines...
January 19, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28099250/interleukin-36%C3%AE-induces-inflammatory-mediators-from-human-pancreatic-myofibroblasts-via-a-myd88-dependent-pathway
#9
Atsushi Nishida, Osamu Inatomi, Takehide Fujimoto, Hirotsugu Imaeda, Masaji Tani, Akira Andoh
OBJECTIVES: Interleukin 36 (IL-36) is a recently described proinflammatory cytokine, characterized by the induction of inflammatory mediators. In the present study, we investigated the biological activity and the signal transduction of IL-36α in human pancreatic myofibroblasts. METHODS: The mRNA and protein expression of inflammatory mediators was evaluated using real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The expression of IL-36α and its receptor in the pancreatic tissue was evaluated using immunohistochemical technique...
January 18, 2017: Pancreas
https://www.readbyqxmd.com/read/28045080/transforming-growth-factor-%C3%AE-activated-kinase-1-transcriptionally-suppresses-hepatitis-b-virus-replication
#10
Jinke Pang, Geng Zhang, Yong Lin, Zhanglian Xie, Hongyan Liu, Libo Tang, Mengji Lu, Ran Yan, Haitao Guo, Jian Sun, Jinlin Hou, Xiaoyong Zhang
Hepatitis B Virus (HBV) replication in hepatocytes is restricted by the host innate immune system and related intracellular signaling pathways. Transforming growth factor β-activated kinase 1 (TAK1) is a key mediator of toll-like receptors and pro-inflammatory cytokine signaling pathways. Here, we report that silencing or inhibition of endogenous TAK1 in hepatoma cell lines leads to an upregulation of HBV replication, transcription, and antigen expression. In contrast, overexpression of TAK1 significantly suppresses HBV replication, while an enzymatically inactive form of TAK1 exerts no effect...
January 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28043920/altered-mir-370-expression-in-hepatic-ischemia-reperfusion-injury-correlates-with-the-level-of-nuclear-kappa-b-nf-%C3%AE%C2%BAb-related-factors
#11
Jie Zhu, Fangfang Zhu, Wenfeng Song, Bin Zhang, Xie Zhang, Xiaofeng Jin, Hong Li
BACKGROUND & AIMS: MicroRNAs (miRNAs) are a class of small endogenous, non-coding RNAs that regulate gene expression at both the transcription and translation levels. Whether miRNAs have taken part in liver ischemia-reperfusion (IR) injury was rarely reported. The purpose of this article is to investigate the potential role of miR-370 in hepatic IR injury. METHODS: Male C57BL/6 mice were divided into 5 groups (sham-operated group, I/R group, IPC group, antagomir-370 group and antagomir-NC), and the expression levels of miR-370 were assessed by quantitative real-time PCR...
April 5, 2017: Gene
https://www.readbyqxmd.com/read/28039475/gpr120-a-potential-therapeutic-target-for-experimental-colitis-in-il-10-deficient-mice
#12
Jie Zhao, Honggang Wang, Peiliang Shi, Wenbo Wang, Ye Sun
It has been proved that interleukin-10-knockout (IL-10 KO) mice display the most similar characteristics to that of human Crohn's disease (CD). Docosahexaenoic acid (DHA) has well established beneficial effects on human and animal models health with potent anti-inflammatory effects with poorly understood mechanisms. This study was aimed at figuring out whether DHA could ameliorate the Crohn's colitis by activating GPR120 and whether GPR120 could be a potential therapeutic target for CD.16 week-old mice included in our present study were divided into three groups, WT group, IL-10 KO group and DHA group(IL-10 KO mice with DHA treatment, i...
January 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/28038940/studies-of-tak1-centered-polypharmacology-with-novel-covalent-tak1-inhibitors
#13
Li Tan, Deepak Gurbani, Ellen L Weisberg, Douglas S Jones, Suman Rao, William D Singer, Faviola M Bernard, Samar Mowafy, Annie Jenney, Guangyan Du, Atsushi Nonami, James D Griffin, Douglas A Lauffenburger, Kenneth D Westover, Peter K Sorger, Nathanael S Gray
Targeted polypharmacology provides an efficient method of treating diseases such as cancer with complex, multigenic causes provided that compounds with advantageous activity profiles can be discovered. Novel covalent TAK1 inhibitors were validated in cellular contexts for their ability to inhibit the TAK1 kinase and for their polypharmacology. Several inhibitors phenocopied reported TAK1 inhibitor 5Z-7-oxozaenol with comparable efficacy and complementary kinase selectivity profiles. Compound 5 exhibited the greatest potency in RAS-mutated and wild-type RAS cell lines from various cancer types...
December 7, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28013046/loss-of-tradd-attenuates-pressure-overload-induced-cardiac-hypertrophy-through-regulating-tak1-p38-mapk-signalling-in-mice
#14
Lianpin Wu, Zhiyong Cao, Ling Ji, Liqin Mei, Qike Jin, Jingjing Zeng, Jiafeng Lin, Maoping Chu, Lei Li, Xiangjun Yang
We investigated the role of tumour necrosis factor receptor (TNFR)-associated death domain (TRADD) on pressure overload-induced cardiac hypertrophy and the underlying molecular mechanisms by using a TRADD deficiency mice model. 6-8 weeks wild-type and TRADD knockout mice were performed to transverse aorta constriction (TAC) or sham operation (6-8 mice for each group). 14 days after TAC, cardiac function was measured by echocardiography, as well as by pathological and molecular analyses of heart samples. The expressions of cardiac hypertrophic and fibrotic markers were detected by qPCR...
December 22, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28011204/structure-guided-development-of-covalent-tak1-inhibitors
#15
Li Tan, Deepak Gurbani, Ellen L Weisberg, John C Hunter, Lianbo Li, Douglas S Jones, Scott B Ficarro, Samar Mowafy, Chun-Pong Tam, Suman Rao, Guangyan Du, James D Griffin, Peter K Sorger, Jarrod A Marto, Kenneth D Westover, Nathanael S Gray
TAK1 (transforming growth factor-β-activated kinase 1) is an essential intracellular mediator of cytokine and growth factor signaling and a potential therapeutic target for the treatment of immune diseases and cancer. Herein we report development of a series of 2,4-disubstituted pyrimidine covalent TAK1 inhibitors that target Cys174, a residue immediately adjacent to the 'DFG-motif' of the kinase activation loop. Co-crystal structures of TAK1 with candidate compounds enabled iterative rounds of structure-based design and biological testing to arrive at optimized compounds...
December 9, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27995356/tripartite-motif-8-trim8-positively-regulates-pro-inflammatory-responses-in-pseudomonas-aeruginosa-induced-keratitis-through-promoting-k63-linked-polyubiquitination-of-tak1-protein
#16
Litao Guo, Weili Dong, Xiaoxiao Fu, Jing Lin, Zhijun Dong, Xiaobo Tan, Tiemin Zhang
Pseudomonas aeruginosa (PA)-induced keratitis is a rapidly progressive ocular infectious disease that often leads to inflammatory epithelial edema, stromal infiltration, tissue destruction, corneal ulceration, and vision loss. In this study, we investigate the role of tripartite motif 8 (TRIM8) in regulating the inflammatory process of PA-induced keratitis. The expression of TRIM8 was increased in mouse corneas and in vitro-cultured macrophages after PA infection. Knockdown of the expression of TRIM8 significantly inhibited the activation of NF-κB signaling and decreased the production of pro-inflammatory cytokines both in vivo and in vitro after infected with PA...
December 19, 2016: Inflammation
https://www.readbyqxmd.com/read/27991595/pgrp-negatively-regulates-nod-mediated-cytokine-production-in-rainbow-trout-liver-cells
#17
Ju Hye Jang, Hyun Kim, Mi Jung Jang, Ju Hyun Cho
Pattern-recognition receptors (PRRs) initiate innate immunity via pathogen recognition. Recent studies suggest that signalling pathways downstream of different PRRs and their crosstalk effectively control immune responses. However, the cross-regulation among PRRs and its effects have yet to be fully described in fish. Here, we examined the crosstalk between OmPGRP-L1, a long form of PGRP in rainbow trout, and other PRRs during pathogenic infections. OmPGRP-L1 expression was increased in RTH-149 cells by iE-DAP and MDP, which are agonists of NOD1 and NOD2, respectively...
December 19, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27986445/nadph-oxidase-4-regulates-vascular-inflammation-in-aging-and-atherosclerosis
#18
Andrey Lozhkin, Aleksandr E Vendrov, Hua Pan, Samuel A Wickline, Nageswara R Madamanchi, Marschall S Runge
We recently reported that increased NADPH oxidase 4 (NOX4) expression and activity during aging results in enhanced cellular and mitochondrial oxidative stress, vascular inflammation, dysfunction, and atherosclerosis. The goal of the present study was to elucidate the molecular mechanism(s) for these effects and determine the importance of NOX4 modulation of proinflammatory gene expression in mouse vascular smooth muscle cells (VSMCs). A novel peptide-mediated siRNA transfection approach was used to inhibit Nox4 expression with minimal cellular toxicity...
December 14, 2016: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/27981609/the-e3-ligase-trim8-targets-tak1-to-promote-insulin-resistance-and-steatohepatitis
#19
Feng-Juan Yan, Xiao-Jing Zhang, Wen-Xin Wang, Yan-Xiao Ji, Pi-Xiao Wang, Yang Yang, Jun Gong, Li-Jun Shen, Xue-Yong Zhu, Zan Huang, Hongliang Li
: Tripartite motif 8 (TRIM8), an E3 ligase ubiquitously expressed in various cells, has been previously identified to be closely involved in innate immunity. However, its role in nonalcoholic steatohepatitis (NASH) is largely unknown. Here, we report the first evidence that TRIM8 is a robust enhancer of steatohepatitis and its complications induced by a high fat diet (HFD) or a genetic deficiency (ob/ob). Using gain- and loss-of-function approaches, we observed dramatic exacerbation of insulin resistance, hepatic steatosis, inflammation, and fibrosis by hepatocyte-specific TRIM8 overexpression, whereas deletion or downregulation of TRIM8 in hepatocytes led to a completely oppose phenotype...
December 16, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/27956576/tripartite-motif-8-contributes-to-pathological-cardiac-hypertrophy-through-enhancing-transforming-growth-factor-%C3%AE-activated-kinase-1-dependent-signaling-pathways
#20
Lijuan Chen, Jia Huang, Yan-Xiao Ji, Fanghua Mei, Pi-Xiao Wang, Ke-Qiong Deng, Xi Jiang, Genshan Ma, Hongliang Li
Tripartite motif (TRIM) 8 functions as an E3 ubiquitin ligase, interacting with and ubiquitinating diverse substrates, and is implicated in various pathological processes. However, the function of TRIM8 in the heart remains largely uncharacterized. This study aims to explore the role of TRIM8 in the development of pathological cardiac hypertrophy. Mice and isolated neonatal rat cardiomyocytes overexpressing or lacking TRIM8 were examined in several experiments. The effect of aortic banding-induced cardiac hypertrophy was analyzed by echocardiographic, pathological and molecular analyses...
December 12, 2016: Hypertension
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